tbuckley/cabot-search huggingface dataset:
T-cell tolerant fraction as a predictor of immune-related adverse events
Authors: Jared Ostmeyer, Jason Y Park, Mitchell S von Itzstein, David Hsiehchen, Farjana Fattah, Mary Gwin, Rodrigo Catalan, Shaheen Khan, Prithvi Raj, Edward K Wakeland, Yang Xie, David E Gerber
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immune checkpoint inhibitor (ICI) therapies may cause unpredictable and potentially severe autoimmune toxicities termed immune-related adverse events (irAEs). Because T cells mediate ICI effects, T cell profiling may provide insight into the risk of irAEs. Here we evaluate a novel metric—the T-cell tolerant fraction—as a predictor of future irAEs. Methods We examined T-cell receptor beta (TRB) locus sequencing from baseline pretreatment samples from an institutional registry and previously published studies. For each patient, we used TRB sequences to calculate the T-cell tolerant fraction, which was then assessed as a predictor of future irAEs (classified as Common Terminology Criteria for Adverse Event grade 0–1 vs grade ≥2). We then compared the tolerant fraction to TRB clonality and diversity. Finally, the tolerant fraction was assessed on (1) T cells enriched against napsin A, a potential autoantigen of irAEs; (2) thymic versus peripheral blood T cells; and (3) TRBs specific for various infections and autoimmune diseases. Results A total of 77 patients with cancer (22 from an institutional registry and 55 from published studies) receiving ICI therapy (43 CTLA4, 19 PD1/PDL1, 15 combination CTLA4+PD1/PDL1) were included in the study. The tolerant fraction was significantly lower in cases with clinically significant irAEs (p&lt;0.001) and had an area under the receiver operating curve (AUC) of 0.79. The tolerant fraction was lower for each ICI treatment category, reaching statistical significance for CTLA4 (p&lt;0.001) and demonstrating non-significant trends for PD1/PDL1 (p=0.21) and combination ICI (p=0.18). The tolerant fraction for T cells enriched against napsin A was lower than other samples. The tolerant fraction was also lower in thymic versus peripheral blood samples, and lower in some (multiple sclerosis) but not other (type 1 diabetes) autoimmune diseases. In our study cohort, TRB clonality had an AUC of 0.62, and TRB diversity had an AUC of 0.60 for predicting irAEs. Conclusions Among patients receiving ICI, the baseline T-cell tolerant fraction may serve as a predictor of clinically significant irAEs.
A novel immune modulator IM33 mediates a glia-gut-neuronal axis that controls lifespan
Authors: Wangchao Xu, Justin Rustenhoven, Christopher A. Nelson, Taitea Dykstra, Aura Ferreiro, Zachary Papadopoulos, Carey-Ann D. Burnham, Gautam Dantas, Daved H. Fremont, Jonathan Kipnis
Journal: Neuron (2023)
Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma
Authors: Mark D. Benson, Aaron S. Eisman, Usman A. Tahir, Daniel H. Katz, Shuliang Deng, Debby Ngo, Jeremy M. Robbins, Alissa Hofmann, Xu Shi, Shuning Zheng, Michelle Keyes, Zhi Yu, Yan Gao, Laurie Farrell, Dongxiao Shen, Zsu-Zsu Chen, Daniel E. Cruz, Mario Sims, Adolfo Correa, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Jie Yao, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, Qiong Yang, Claude Bouchard, Mark A. Sarzynski, Stephen S. Rich, Jerome I. Rotter, Thomas J. Wang, James G. Wilson, Clary B. Clish, Indra Neil Sarkar, Pradeep Natarajan, Robert E. Gerszten
Journal: Cell Metabolism (2023)
Prioritization of therapeutic targets for dyslipidemia using integrative multi-omics and multi-trait analysis
Authors: Min Seo Kim, Minku Song, Beomsu Kim, Injeong Shim, Dan Say Kim, Pradeep Natarajan, Ron Do, Hong-Hee Won
Journal: Cell Reports Medicine (2023)

Drug targets with genetic support are several-fold more likely to succeed in clinical trials. We introduce a genetic-driven approach based on causal inferences that can inform drug target prioritization, repurposing, and adverse effects of using lipid-lowering agents. Given that a multi-trait approach increases the power to detect meaningful variants/genes, we conduct multi-omics and multi-trait analyses, followed by network connectivity investigations, and prioritize 30 potential therapeutic targets for dyslipidemia, including SORT1, PSRC1, CELSR2, PCSK9, HMGCR, APOB, GRN, HFE2, FJX1, C1QTNF1, and SLC5A8. 20% (6/30) of prioritized targets from our hypothesis-free drug target search are either approved or under investigation for dyslipidemia. The prioritized targets are 22-fold higher in likelihood of being approved or under investigation in clinical trials than genome-wide association study (GWAS)-curated targets. Our results demonstrate that the genetic-driven approach used in this study is a promising strategy for prioritizing targets while informing about the potential adverse effects and repurposing opportunities.
Human microglia maturation is underpinned by specific gene regulatory networks
Authors: Claudia Z. Han, Rick Z. Li, Emily Hansen, Samantha Trescott, Bethany R. Fixsen, Celina T. Nguyen, Cristina M. Mora, Nathanael J. Spann, Hunter R. Bennett, Olivier Poirion, Justin Buchanan, Anna S. Warden, Bing Xia, Johannes C.M. Schlachetzki, Martina P. Pasillas, Sebastian Preissl, Allen Wang, Carolyn O’Connor, Shreya Shriram, Roy Kim, Danielle Schafer, Gabriela Ramirez, Jean Challacombe, Samuel A. Anavim, Avalon Johnson, Mihir Gupta, Ian A. Glass, Michael L. Levy, Sharona Ben Haim, David D. Gonda, Louise Laurent, Jennifer F. Hughes, David C. Page, Mathew Blurton-Jones, Christopher K. Glass, Nicole G. Coufal
Journal: Immunity (2023)

Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes.
Transcriptomic analysis of cutaneous squamous cell carcinoma reveals a multigene prognostic signature associated with metastasis
Authors: Jun Wang, Catherine A. Harwood, Emma Bailey, Findlay Bewicke-Copley, Chinedu Anthony Anene, Jason Thomson, Mah Jabeen Qamar, Rhiannon Laban, Craig Nourse, Christina Schoenherr, Mairi Treanor-Taylor, Eugene Healy, Chester Lai, Paul Craig, Colin Moyes, William Rickaby, Joanne Martin, Charlotte Proby, Gareth J. Inman, Irene M. Leigh
Journal: Journal of the American Academy of Dermatology (2023)

Metastasis of cutaneous squamous cell carcinoma (cSCC) is uncommon. Current staging methods are reported to have sub-optimal performances in metastasis prediction. Accurate identification of patients with tumors at high risk of metastasis would have a significant impact on management.
Targeting the blood–brain barrier to delay aging-accompanied neurological diseases by modulating gut microbiota, circadian rhythms, and their interplays
Authors: Yanping Wang, Weihong Du, Xiaoyan Hu, Xin Yu, Chun Guo, Xinchun Jin, Wei Wang
Journal: Acta Pharmaceutica Sinica B (2023)

The blood–brain barrier (BBB) impairment plays a crucial role in the pathological processes of aging-accompanied neurological diseases (AAND). Meanwhile, circadian rhythms disruption and gut microbiota dysbiosis are associated with increased morbidity of neurological diseases in the accelerated aging population. Importantly, circadian rhythms disruption and gut microbiota dysbiosis are also known to induce the generation of toxic metabolites and pro-inflammatory cytokines, resulting in disruption of BBB integrity. Collectively, this provides a new perspective for exploring the relationship among circadian rhythms, gut microbes, and the BBB in aging-accompanied neurological diseases. In this review, we focus on recent advances in the interplay between circadian rhythm disturbances and gut microbiota dysbiosis, and their potential roles in the BBB disruption that occurs in AAND. Based on existing literature, we discuss and propose potential mechanisms underlying BBB damage induced by dysregulated circadian rhythms and gut microbiota, which would serve as the basis for developing potential interventions to protect the BBB in the aging population through targeting the BBB by exploiting its links with gut microbiota and circadian rhythms for treating AAND.
Gene augmentation therapy attenuates retinal degeneration in a knockout mouse model of Fam161a retinitis pigmentosa
Authors: Chen Matsevich, Prakadeeswari Gopalakrishnan, Ning Chang, Alexey Obolensky, Avigail Beryozkin, Manar Salameh, Corinne Kostic, Dror Sharon, Yvan Arsenijevic, Eyal Banin
Journal: Molecular Therapy (2023)
Emerging drug design strategies in anti-influenza drug discovery
Authors: Chuanfeng Liu, Lide Hu, Guanyu Dong, Ying Zhang, Edeildo Ferreira da Silva-Júnior, Xinyong Liu, Luis Menéndez-Arias, Peng Zhan
Journal: Acta Pharmaceutica Sinica B (2023)

Influenza is an acute respiratory infection caused by influenza viruses (IFV), According to the World Health Organization (WHO), seasonal IFV epidemics result in approximately 3–5 million cases of severe illness, leading to about half a million deaths worldwide, along with severe economic losses and social burdens. Unfortunately, frequent mutations in IFV lead to a certain lag in vaccine development as well as resistance to existing antiviral drugs. Therefore, it is of great importance to develop anti-IFV drugs with high efficiency against wild-type and resistant strains, needed in the fight against current and future outbreaks caused by different IFV strains. In this review, we summarize general strategies used for the discovery and development of antiviral agents targeting multiple IFV strains (including those resistant to available drugs). Structure-based drug design, mechanism-based drug design, multivalent interaction-based drug design and drug repurposing are amongst the most relevant strategies that provide a framework for the development of antiviral drugs targeting IFV.
High Exposure to Perfluoroalkyl Substances and Antibody Responses to SARS-CoV-2 mRNA Vaccine—an Observational Study in Adults from Ronneby, Sweden
Authors: Axel G. Andersson, Anna Lundgren, Yiyi Xu, Christel Nielsen, Christian H. Lindh, Daniela Pineda, Julia Cederlund, Elisavet Pataridou, Sandra Søgaard Tøttenborg, Kajsa Ugelvig Petersen, Tony Fletcher, Martin Lagging, Mats Bemark, Kristina Jakobsson, Ying Li
Journal: Environmental Health Perspectives (2023)

Per- and polyfluoroalkyl substances (PFAS) are widely used, environmentally ubiquitous, and stable chemicals that have been associated with lower vaccine-induced antibody responses in children; however, data on adults are limited. The drinking water from one of the two waterworks in Ronneby, Sweden, was heavily contaminated for decades with PFAS from firefighting foams, primarily perfluorohexane sulfonic acid and perfluorooctanesulfonic acid (PFOS). Vaccination against SARS-CoV-2 offered a unique opportunity to investigate antibody responses to primary vaccination in adults who had been exposed to PFAS.
Development and validation of a novel risk prediction algorithm to estimate 10-year risk of oesophageal cancer in primary care: prospective cohort study and evaluation of performance against two other risk prediction models
Authors: Julia Hippisley-Cox, Winnie Mei, Rebecca Fitzgerald, Carol Coupland
Journal: The Lancet Regional Health - Europe (2023)

Methods to identify patients at increased risk of oesophageal cancer are needed to better identify those for targeted screening. We aimed to derive and validate novel risk prediction algorithms (CanPredict) to estimate the 10-year risk of oesophageal cancer and evaluate performance against two other risk prediction models. Prospective open cohort study using routinely collected data from 1804 QResearch® general practices. We used 1354 practices (12.9 M patients) to develop the algorithm. We validated the algorithm in 450 separate practices from QResearch (4.12 M patients) and 355 Clinical Practice Research Datalink (CPRD) practices (2.53 M patients). The primary outcome was an incident diagnosis of oesophageal cancer found in GP, mortality, hospital, or cancer registry data. Patients were aged 25–84 years and free of oesophageal cancer at baseline. Cox proportional hazards models were used with prediction selection to derive risk equations. Risk factors included age, ethnicity, Townsend deprivation score, body mass index (BMI), smoking, alcohol, family history, relevant co-morbidities and medications. Measures of calibration, discrimination, sensitivity, and specificity were calculated in the validation cohorts. There were 16,384 incident cases of oesophageal cancer in the derivation cohort (0.13% of 12.9 M). The predictors in the final algorithms were: age, BMI, Townsend deprivation score, smoking, alcohol, ethnicity, Barrett's oesophagus, hiatus hernia, H. pylori infection, use of proton pump inhibitors, anaemia, lung and blood cancer (with breast cancer in women). In the QResearch validation cohort in women the explained variation (R2) was 57.1%; Royston's D statistic 2.36 (95% CI 2.26–2.46); C statistic 0.859 (95% CI 0.849–0.868) and calibration was good. Results were similar in men. For the 20% at highest predicted risk, the sensitivity was 76%, specificity was 80.1% and the observed risk at 10 years was 0.76%. The results from the CPRD validation were similar. We have developed and validated a novel prediction algorithm to quantify the absolute risk of oesophageal cancer. The CanPredict algorithms could be used to identify high risk patients for targeted screening. Innovate UK and CRUK (grant 105857).
From oncolytic peptides to oncolytic polymers: A new paradigm for oncotherapy
Authors: Hanmeng Liu, Wei Shen, Wanguo Liu, Zexin Yang, Dengke Yin, Chunsheng Xiao
Journal: Bioactive Materials (2023)

Traditional cancer therapy methods, especially those directed against specific intracellular targets or signaling pathways, are not powerful enough to overcome tumor heterogeneity and therapeutic resistance. Oncolytic peptides that can induce membrane lysis-mediated cancer cell death and subsequent anticancer immune responses, has provided a new paradigm for cancer therapy. However, the clinical application of oncolytic peptides is always limited by some factors such as unsatisfactory bio-distribution, poor stability, and off-target toxicity. To overcome these limitations, oncolytic polymers stand out as prospective therapeutic materials owing to their high stability, chemical versatility, and scalable production capacity, which has the potential to drive a revolution in cancer treatment. This review provides an overview of the mechanism and structure-activity relationship of oncolytic peptides. Then the oncolytic peptides-mediated combination therapy and the nano-delivery strategies for oncolytic peptides are summarized. Emphatically, the current research progress of oncolytic polymers has been highlighted. Lastly, the challenges and prospects in the development of oncolytic polymers are discussed.
Ultrasound-triggered biomimetic ultrashort peptide nanofiber hydrogels promote bone regeneration by modulating macrophage and the osteogenic immune microenvironment
Authors: Fan Zhang, Mingchen Lv, Siyuan Wang, Mengyao Li, Yu Wang, Congjiao Hu, Wei Hu, Xuekui Wang, Xiaogang Wang, Zhiduo Liu, Zhen Fan, Jianzhong Du, Yao Sun
Journal: Bioactive Materials (2023)

The immune microenvironment plays a vital role in bone defect repair. To create an immune microenvironment that promotes osteogenesis, researchers are exploring ways to enhance the differentiation of M2-type macrophages. Functional peptides have been discovered to effectively improve this process, but they are limited by low efficiency and rapid degradation
Clinical Outcomes of Direct Oral Anticoagulants vs Warfarin for Extended Treatment of Venous Thromboembolism
Authors: Margaret C. Fang, Kristi Reynolds, Dongjie Fan, Priya A. Prasad, Sue Hee Sung, Cecilia Portugal, Elisha Garcia, Alan S. Go
Journal: JAMA Network Open (2023)

Extending the duration of oral anticoagulation for venous thromboembolism (VTE) beyond the initial 3 to 6 months of treatment is often recommended, but it is not clear whether clinical outcomes differ when using direct oral anticoagulants (DOACs) or warfarin.To compare rates of recurrent VTE, hospitalizations for hemorrhage, and all-cause death among adults prescribed DOACs or warfarin whose anticoagulant treatment was extended beyond 6 months after acute VTE.This cohort study was conducted in 2 integrated health care delivery systems in California with adults aged 18 years or older who received a diagnosis of incident VTE between 2010 and 2018 and completed at least 6 months of oral anticoagulant treatment with DOACs or warfarin. Patients were followed from the end of the initial 6-month treatment period until discontinuation of anticoagulation, occurrence of an outcome event, health plan disenrollment, or end of the study follow-up period (December 31, 2019). Data were obtained from the Kaiser Permanente Virtual Data Warehouse and electronic health records. Data analysis was conducted from March 2022 to January 2023.Dispensed prescriptions of DOACs or warfarin after a 6-month initial treatment for VTE.The primary outcomes were rates per 100 person-years of recurrent VTE, hospitalizations for hemorrhage, and all-cause death. Comparison of DOAC and warfarin outcomes were performed using multivariable Cox proportional hazards regression.A total of 18 495 patients (5477 [29.6%] aged ≥75 years; 8973 women [48.5%]) with VTE who were treated with at least 6 months of anticoagulation were identified, of whom 2134 (11.5%) were receiving DOAC therapy and 16 361 (88.5%) were receiving warfarin therapy. Unadjusted event rates were lower for patients receiving DOAC therapy than warfarin therapy for recurrent VTE (event rate per 100 person-years, 2.92 [95% CI, 2.29-3.54] vs 4.14 [95% CI, 3.90-4.38]), hospitalizations for hemorrhage (event rate per 100 person-years, 1.02 [95% CI, 0.66-1.39] vs 1.81 [95% CI, 1.66-1.97]), and all-cause death (event rate per 100 person-years, 3.79 [95% CI, 3.09-4.49] vs 5.40 [95% CI, 5.13-5.66]). After multivariable adjustment, DOAC treatment was associated with a lower risk of recurrent VTE (adjusted hazard ratio [aHR], 0.66; 95% CI, 0.52-0.82). For patients prescribed DOAC treatment, the risks of hospitalization for hemorrhage (aHR, 0.79; 95% CI, 0.54-1.17) and all-cause death (aHR, 0.96; 95% CI, 0.78-1.19) were not significantly different than those for patients prescribed warfarin treatment.In this cohort study of patients with VTE who continued warfarin or DOAC anticoagulation beyond 6 months, DOAC treatment was associated with a lower risk of recurrent VTE, supporting the use of DOACs for the extended treatment of VTE in terms of clinical outcomes.
SPOP Mutations Target STING1 Signaling in Prostate Cancer and Create Therapeutic Vulnerabilities to PARP Inhibitor–Induced Growth Suppression
Authors: Chuandong Geng, Man-Chao Zhang, Ganiraju C. Manyam, Jody V. Vykoukal, Johannes F. Fahrmann, Shan Peng, Cheng Wu, Sanghee Park, Shakuntala Kondraganti, Daoqi Wang, Brian D. Robinson, Massimo Loda, Christopher E. Barbieri, Timothy A. Yap, Paul G. Corn, Samir Hanash, Bradley M. Broom, Patrick G. Pilié, Timothy C. Thompson
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Speckle-type POZ protein (SPOP) is important in DNA damage response (DDR) and maintenance of genomic stability. Somatic heterozygous missense mutations in the SPOP substrate-binding cleft are found in up to 15% of prostate cancers. While mutations in SPOP predict for benefit from androgen receptor signaling inhibition (ARSi) therapy, outcomes for patients with SPOP-mutant (SPOPmut) prostate cancer are heterogeneous and targeted treatments for SPOPmut castrate-resistant prostate cancer (CRPC) are lacking. Experimental Design: Using in silico genomic and transcriptomic tumor data, proteomics analysis, and genetically modified cell line models, we demonstrate mechanistic links between SPOP mutations, STING signaling alterations, and PARP inhibitor vulnerabilities. Results: We demonstrate that SPOP mutations are associated with upregulation of a 29-gene noncanonical (NC) STING (NC-STING) signature in a subset of SPOPmut, treatment-refractory CRPC patients. We show in preclinical CRPC models that SPOP targets and destabilizes STING1 protein, and prostate cancer–associated SPOP mutations result in upregulated NC-STING–NF-κB signaling and macrophage- and tumor microenvironment (TME)–facilitated reprogramming, leading to tumor cell growth. Importantly, we provide in vitro and in vivo mechanism-based evidence that PARP inhibitor (PARPi) treatment results in a shift from immunosuppressive NC-STING–NF-κB signaling to antitumor, canonical cGAS–STING–IFNβ signaling in SPOPmut CRPC and results in enhanced tumor growth inhibition. Conclusions: We provide evidence that SPOP is critical in regulating immunosuppressive versus antitumor activity downstream of DNA damage–induced STING1 activation in prostate cancer. PARPi treatment of SPOPmut CRPC alters this NC-STING signaling toward canonical, antitumor cGAS–STING–IFNβ signaling, highlighting a novel biomarker-informed treatment strategy for prostate cancer.
Updating Evidence for Treatment of Pelvic Organ Prolapse
Authors: Charles W. Nager
Journal: JAMA (2023)

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Diagnosis and management of patients with left ventricular hypertrophy: Role of multimodality cardiac imaging. A scientific statement of the Heart Failure Association of the European Society of Cardiology
Authors: Brenda Moura, Alberto Aimo, Abdallah Al‐Mohammad, Kalliopi Keramida, Tuvia Ben Gal, Sharmila Dorbala, Giancarlo Todiere, Matteo Cameli, Andrea Barison, Antoni Bayes‐Genis, Ralph Stephan von Bardeleben, Chiara Bucciarelli‐Ducci, Victoria Delgado, Ify R. Mordi, Petar Seferovic, Gianluigi Savarese, Jelena Čelutkienė, Claudio Rapezzi, Michele Emdin, Andrew Coats, Marco Metra, Giuseppe Rosano
Journal: European Journal of Heart Failure (2023)